Knaup, Fabian Henrik (2023)
Synthesis and investigation of 2-substituted hetero-/arylacetic acids as bottom groups for selective inhibitors of the FK506-binding protein 51 (FKBP51).
Technische Universität Darmstadt
doi: 10.26083/tuprints-00023707
Dissertation, Erstveröffentlichung, Verlagsversion
Kurzbeschreibung (Abstract)
In recent years the FK506-binding protein 51 (FKBP51) has emerged as a potential target for treating depression, chronic pain, or diabetes. The first selective FKBP51 inhibitors, SAFit1 and SAFit2, contain a crucial cyclohexyl group in the bottom group section, enabling selectivity over the closest homolog FKBP52. After discovering these lead compounds, all structure-based optimizations were conducted in the context of the cyclohexyl group for inducing selectivity for FKBP51. Therefore, first, different approaches for synthesizing 2,2-disubstituted acetic acids were investigated, and the respective SAFit1 analogs were analyzed by structure-affinity relationships. During the structure-based optimization of the SAFit bottom group to enhance the overall physicochemical properties and metabolic stability, a thiophene scaffold was identified that could enable selectivity for FKBP51. For the first time since the discovery of the SAFit ligands, a suitable replacement for the highly efficient cyclohexyl motif was identified. Additionally, thiophene-containing SAFit analogs have a high binding affinity for FKBP51 and can discriminate between FKBP51 and its closest homolog, FKBP52. The co-crystal structures of those analogs also revealed that the novel scaffold enables selectivity by binding to the previously identified transient binding pocket, which is characterized by the displacement of the phenylalanine residue in position 67 towards the solvent phase. Moreover, besides high binding affinity and selectivity for FKBP51, the most promising SAFit2 analog 68b of this series also possesses an acceptable pharmacokinetic profile in-vivo. As a result, the thiophene-containing SAFit2 analogs are promising tool compounds for investigating FKBP51 in animal models.
| Typ des Eintrags: | Dissertation | ||||
|---|---|---|---|---|---|
| Erschienen: | 2023 | ||||
| Autor(en): | Knaup, Fabian Henrik | ||||
| Art des Eintrags: | Erstveröffentlichung | ||||
| Titel: | Synthesis and investigation of 2-substituted hetero-/arylacetic acids as bottom groups for selective inhibitors of the FK506-binding protein 51 (FKBP51) | ||||
| Sprache: | Englisch | ||||
| Referenten: | Hausch, Prof. Dr. Felix ; Kolmar, Prof. Dr. Harald | ||||
| Publikationsjahr: | 2023 | ||||
| Ort: | Darmstadt | ||||
| Kollation: | IX, 257 Seiten | ||||
| Datum der mündlichen Prüfung: | 17 April 2023 | ||||
| DOI: | 10.26083/tuprints-00023707 | ||||
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/23707 | ||||
| Kurzbeschreibung (Abstract): | In recent years the FK506-binding protein 51 (FKBP51) has emerged as a potential target for treating depression, chronic pain, or diabetes. The first selective FKBP51 inhibitors, SAFit1 and SAFit2, contain a crucial cyclohexyl group in the bottom group section, enabling selectivity over the closest homolog FKBP52. After discovering these lead compounds, all structure-based optimizations were conducted in the context of the cyclohexyl group for inducing selectivity for FKBP51. Therefore, first, different approaches for synthesizing 2,2-disubstituted acetic acids were investigated, and the respective SAFit1 analogs were analyzed by structure-affinity relationships. During the structure-based optimization of the SAFit bottom group to enhance the overall physicochemical properties and metabolic stability, a thiophene scaffold was identified that could enable selectivity for FKBP51. For the first time since the discovery of the SAFit ligands, a suitable replacement for the highly efficient cyclohexyl motif was identified. Additionally, thiophene-containing SAFit analogs have a high binding affinity for FKBP51 and can discriminate between FKBP51 and its closest homolog, FKBP52. The co-crystal structures of those analogs also revealed that the novel scaffold enables selectivity by binding to the previously identified transient binding pocket, which is characterized by the displacement of the phenylalanine residue in position 67 towards the solvent phase. Moreover, besides high binding affinity and selectivity for FKBP51, the most promising SAFit2 analog 68b of this series also possesses an acceptable pharmacokinetic profile in-vivo. As a result, the thiophene-containing SAFit2 analogs are promising tool compounds for investigating FKBP51 in animal models. |
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| Alternatives oder übersetztes Abstract: |
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| Status: | Verlagsversion | ||||
| URN: | urn:nbn:de:tuda-tuprints-237078 | ||||
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie | ||||
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie |
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| Hinterlegungsdatum: | 27 Apr 2023 12:06 | ||||
| Letzte Änderung: | 28 Apr 2023 05:26 | ||||
| PPN: | |||||
| Referenten: | Hausch, Prof. Dr. Felix ; Kolmar, Prof. Dr. Harald | ||||
| Datum der mündlichen Prüfung / Verteidigung / mdl. Prüfung: | 17 April 2023 | ||||
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